The His723Arg (H723R) mutation in SLC26A4, encoding pendrin, is the most prevalent mutation in East Asia, resulting in DFNB4, an autosomal recessive type of genetic hearing loss. Although the main pathological mechanism of H723R was identified as a protein-folding defect in pendrin, there is still no curative treatment for associated hearing loss. Here, we show that H723R-pendrin expression and activity are rescued by activation of the chaperonin DNAJC14. In vitro, DNAJC14 was activated via Japanese encephalitis virus (JEV) inoculation, and toxin-attenuated JEV rescued the surface expression and anion exchange activity of H723R-pendrin. Human H723R-pendrin transgenic mice (hH723R Tg) were established in a mouse slc26a4 knockout background, in which only hH723R-pendrin was expressed in the inner ear (Pax2-Cre dependent) to mimic human DFNB4 pathology. Crossing hH723R Tg with DNAJC14-overexpressing mice resulted in reduced cochlear hydrops and more preserved outer hair cells in the cochlea compared to those in hH723R Tg mice. Furthermore, the stria vascularis and spiral ligament were thicker and KCNJ10 expression was increased with DNAJC14 overexpression; however, hearing function and enlarged endolymphatic hydrops were not recovered. These results indicate that DNAJC14 overexpression ameliorates the cochlear degeneration caused by misfolded pendrin and might be a potential therapeutic target for DFNB4.

中文翻译：

---

DNAJC14改善了DFNB4小鼠模型中的内耳变性。

SLC26A4中的编码Pendrin的His723Arg（H723R）突变是东亚地区最普遍的突变，导致了DFNB4（一种常染色体隐性遗传性听力损失）。尽管H723R的主要病理机制被确定为Pendrin中的蛋白质折叠缺陷，但仍没有治愈相关听力损失的治疗方法。在这里，我们显示通过伴侣蛋白DNAJC14的活化可以拯救H723R-pendrin的表达和活性。在体外，通过日本脑炎病毒（JEV）接种激活了DNAJC14，毒素减毒JEV拯救了H723R-Pendrin的表面表达和阴离子交换活性。在小鼠slc26a4基因敲除背景下建立了人类H723R-pendrin转基因小鼠（hH723R Tg），其中仅hH723R-pendrin在内耳中表达（依赖Pax2-Cre），以模仿人类DFNB4病理。与hH723R Tg小鼠相比，将hH723R Tg与过表达DNAJC14的小鼠杂交可减少耳蜗积液，并保留更多的保留在耳蜗中的外毛细胞。此外，DNAJC14过表达使血管纹和螺旋韧带增厚，KCNJ10表达增加。然而，听觉功能和淋巴结内积液扩大并没有恢复。这些结果表明，DNAJC14的过表达改善了因错误折叠的Pendrin引起的耳蜗变性，并且可能是DFNB4的潜在治疗靶标。此外，DNAJC14过表达使血管纹和螺旋韧带增厚，KCNJ10表达增加。然而，听觉功能和淋巴结内积液扩大并没有恢复。这些结果表明，DNAJC14的过表达改善了因错误折叠的Pendrin引起的耳蜗变性，可能是DFNB4的潜在治疗靶标。此外，DNAJC14过表达使血管纹和螺旋韧带增厚，KCNJ10表达增加。然而，听觉功能和淋巴结内积液扩大并没有恢复。这些结果表明，DNAJC14的过表达改善了因错误折叠的Pendrin引起的耳蜗变性，并且可能是DFNB4的潜在治疗靶标。